Updated diagnostic criteria for Alzheimer's disease will allow physicians to identify patients in the earliest possible stages of the disease, capitalizing on the treatments now available and enriching the research into new therapies.
The proposed criteria, which were unveiled at the conference in July, are the first updates to the diagnosis of Alzheimer's disease in 25 years.
While some of the proposed changes will have an immediate clinical impact if they are accepted, most are aimed at helping to create a future in which early diagnosis—well before any cognitive symptoms appear—will allow optimal use of yet-to-be-developed disease-modifying agents.
“We already have evidence that biomarkers and imaging can suggest that amyloid is accumulating in the brain years—even decades—before symptoms appear,” Dr. Reisa Sperling, director of clinical research at the Memory Disorders Unit, Brigham and Women's Hospital, Boston, said in an Aug. 4 teleconference sponsored by the Alzheimer's Association. “But at this point we don't know what it means to have amyloid in the brain with no symptoms. These criteria will help us identify and study these patients to determine if they do develop the disease, and any factors that might mediate the progression.”
The biomarkers identified in the new criteria are not ready for use in the medical community,” said Dr. Marilyn Albert, Ph.D., director of the division of cognitive neuroscience at Johns Hopkins Medical Center, Baltimore. Although both biochemical and imaging biomarkers have been widely used in research settings, “only now are large collaborative studies giving us an idea of how to standardize what we are seeing.”
Once standardization occurs and norms are established, “we will be able to identify people at risk of developing Alzheimer's down the line and these are the people we want to treat, when we have an effective medication,” she said.
The update is the first major overhaul since the original diagnostic criteria were established in 1984. However, in 2007, Dr. Bruno Dubois of the Université Pierre et Marie Curie–Paris, and his colleagues suggested that the criteria were miserably outdated, and failed to incorporate any of the rapidly exploding clinical research.
His proposal for a new set of diagnostic criteria was based on a clinical finding of early, significant episodic memory impairment, along with at least one abnormal biomarker (structural neuroimaging with MRI, molecular neuroimaging with PET, and cerebrospinal fluid analysis of beta-amyloid or tau proteins).
“The timeliness of these criteria is highlighted by the many drugs in development that are directed at changing pathogenesis, particularly at the production and clearance of beta amyloid as well as at the hyperphosphorylation state of tau,” Dr. Dubois and his colleagues wrote (Lancet Neurol. 2007;6:734-46). “Validation studies in existing and prospective cohorts are needed to advance these criteria and optimize their sensitivity, specificity, and accuracy.”
Although the Dubois criteria sparked a renewed interest in incorporating research findings into diagnosis, they were never fully adopted by influential organizations. Last year, the National Institute on Aging and the Alzheimer's Association agreed to examine how to better incorporate new knowledge into the 1984 criteria. The agencies created work groups to explore this idea in three stages of the disease process: preclinical, mild cognitive impairment, and Alzheimer's dementia.
Dr. Sperling headed the preclinical group. “For me, this is the most exciting area, because it's the newest,” she said in an interview during the conference in Honolulu. “We have never tried to set criteria to diagnose Alzheimer's before there is significant clinical impairment.”
And yet, she said, this period may be the most crucial, for two reasons. First, because the earlier existing treatments are employed, the more effective they are. Second, because identifying a prodromal stage of Alzheimer's will eventually be key to developing new therapies.
Alzheimer's has never been viewed as a disease with an identifiable, but asymptomatic, prodromal state. “In most other chronic diseases, we recognize that there is a preclinical stage—carcinoma in situ, for example, or high cholesterol that can be detected far in advance of a heart attack. We desperately need to move Alzheimer's to that kind of continuum, because our best chance at treating the disease and changing its course will be to treat before any symptoms appear, or when there are only very mild symptoms,” Dr. Sperling said.
The preclinical group identified three diagnostic criteria for the earliest stage of Alzheimer's:
▸ Asymptomatic amyloidosis, defined by evidence of abnormal levels of amyloid in the spinal fluid or on a brain scan, but no cognitive or functional symptoms.
▸ Amyloidosis plus one other marker of disease, which could be brain atrophy on imaging, functional abnormalities, or abnormal levels of phosphorylated tau in spinal fluid.
▸ Amyloidosis plus a biomarker and slight cognitive symptoms. “This may be the most important stage, because there is good evidence that people experience cognitive changes years before they progress to mild cognitive impairment,” Dr. Sperling said. “Right now, we can't differentiate normal aging from the very beginning of Alzheimer's. But the combination of these biomarkers and memory trouble will allow us to predict who is on the Alzheimer's trajectory.”
Research may especially benefit from this identification, because drugs to slow or halt disease progression will be most effective in patients with the least neuronal damage, she added.
The work group that examined diagnostic criteria for mild cognitive impairment (MCI) also identified three criteria:
▸ The already-established clinical syndrome of MCI in which patients are aware of their memory problem and have a measurable deficit, but other cognitive and functional skills are preserved.
▸ In addition to MCI, there is some evidence of change in brain topography—either hippocampal atrophy or hypometabolic brain regions.
▸ In addition to MCI and topographical brain changes, a confirmed measure of amyloid abnormality, including reduced beta-amyloid 42 in cerebrospinal fluid (indicating its accumulation in the brain) or positive amyloid brain imaging.
“This represents the progression in a perfect world,” said Dr. Ronald Peterson, a member of the MCI work group and director of the Mayo Clinic Alzheimer's Disease Research Center in Rochester, Minn. “But the devil is in the details. What if you have the clinical syndrome but your biomarkers go in the opposite direction, or you have an incomplete set? That is where research is going to fill in the gaps in our knowledge.”
Dr. John Morris, director of the Alzheimer's Disease Research Center at Washington University, St. Louis, is a member of the dementia working group. Because diagnostic algorithms for dementia were already in place—albeit 25 years old—his group made modifications to the existing criteria.
“With the addition of biomarkers to support the clinical suspicion of dementia, we have been able to strengthen those criteria substantially, giving physicians the ability to be much more confident in their diagnoses,” Dr. Morris said in an interview.
Previously, the only way to obtain a definitive Alzheimer's disease diagnosis was through brain autopsy; the presence of amyloid plaques and neurofibrillary tangles has been the key diagnostic feature. “With these strengthened criteria, we can now diagnose it in a living person.”
Documented and measurable memory deficits in the presence of at least one biomarker now correlates to the diagnosis of “probable Alzheimer's.” In addition to memory deficits, the presence of several biomarkers—structural brain changes, functional brain changes, positive amyloid imaging, spinal fluid abnormalities, or genetic markers—can strengthen the diagnosis of probable disease.
The presence of a genetic marker in this mix, especially the apolipoprotein E e4 allele, equates to a definitive diagnosis.
The work groups are now seeking feedback on the criteria. Comments can be submitted to the Alzheimer's Association Web site (www.alz.org/research/diagnostic_criteria), which is hosting the criteria.
“We'll take this, go back to the drawing board and hammer out the fine details,” Dr. Peterson said in an interview. “In the fall, there will probably be three papers—one for each of the workgroups—published in the Alzheimer's Association journal, Alzheimer's and Dementia.”
The criteria may supply the key component in the “chicken or egg” problem that has plagued Alzheimer's research for years: New treatments will almost certainly be most effective in the earliest stage of the disease, and therefore must be tested in those patients. But researchers have been unable to identify those patients who are the best candidates for new treatment research.
“By the time symptoms appear, there has already been substantial neuronal loss in critical brain areas, and it's been impossible to arrest the disease once this damage has occurred,” Dr. Morris said. “It makes great sense to intervene earlier—even before MCI—to see if we can treat with the hope of preventing disease progression. The Holy Grail would be to prevent damage before it ever appears, but we need to be able to find and treat those people who are on the Alzheimer's path, before they begin to have symptoms.”
The project was funded by the National Institute on Aging and the Alzheimer's Association. None of the physicians reported any potential financial conflicts.
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